Epstein-Barr virus (EBV) is associated with a number of human malignancies for which there are presently few effective treatments. Lymphoid malignancies caused by, or associated with, Epstein-Barr virus include Burkitt's lymphoma, T/NK lymphomas, some T- and B-cell lymphomas, approximately half of Hodgkin's lymphomas and all post-transplant lymphoproliferative disorders (LPD). EBV(+) T and T/NK lymphomas in particular generally have an ominous prognosis, as does LPD if monoclonal. Solid tumors associated with the presence of latent EBV include nasopharyngeal carcinoma (NPC), gastric cancer, and breast cancer. The key to EBV's prevalence is its ability to persist in a dormant or "latent" state. EBV is a Herpesvirus, and many Herpes-family virus-infected cells can be killed by nucleoside analog antiviral drugs like ganciclovir, which target the viral thymidine kinase (TK) enzyme. Unlike other members of the Herpesvirus family, however, EBV is resistant to these antiviral agents, because latently-infected cells do not express the viral (TK) enzyme. We have demonstrated in in vitro assays on human tumor cells that selected agents which induce the EBV TK gene expression in these cells renders them susceptible to standard anti-viral agents. We then conducted and published a Phase I/II study to determine the tolerability/toxicity and efficacy of combined TK-inducing agent plus ganciclovir (IND #47,529) in 15 patients with EBV-associated lymphomas or LPD, all of which were completely resistant to conventional radiation and chemotherapy. Our targeted therapy produced complete clinical responses (CRs) in 4/15 patients, and good partial responses (PRs) in an additional 6 patients (total response rate of 67%). This is a truly targeted therapy, in that only the tumor cells (containing EBV) are killed -- normal cells are spared. This novel therapeutic strategy thus identified a novel target (a cancer-associated virus) present only in the tumor cells, and utilized pharmacological induction of a viral protein to make the cells susceptible to a conventional anti-viral agent. The unique features of the strategy include the molecular target and the specificity of the approach (virus-negative [normal] cells will be spared. The only major limitation of the current therapeutic regimen is that the drug used to induce the virus must be given by continuous IV infusion, in hospital, over many days. This proposal will identify and test much more active inducers of the TK gene, which can be administered on a more convenient basis, to improve this targeted therapeutic approach. We will focus specifically on short-chain fatty acid derivatives (SCFAD) or HDAC inhibitors which are approved or nearing approval, have superior pharmacokinetics, and are more selective in their actions on the EBV TK gene than our current generation drug. We will also select the optimal nucleoside anti-viral for EBV-selective tumor cytotoxicity. Selected inducers will be tested in combination with the optimal anti-viral agent in a mouse model of human EBV+ cancer. The outcome will be a more potent, selective, and more widely-accessibly therapy for EBV+ cancers and LPD. PUBLIC HEALTH RELEVANCE: Latent Epstein-Barr virus (EBV) is associated with a number of human malignancies and lymphoid proliferative diseases for which there are presently few effective treatments. We have developed a novel virus-targeted therapeutic approach, combining an agent to induce the virus out of latency together with an approved anti-viral agent, to treat these malignancies and lymphoid proliferative diseases, and have demonstrated safety and significant efficacy in a Phase I/II clinical trial. We propose here to identify a more potent and optimized inducing agent and antiviral agent, and demonstrate their anti-tumor activity in an animal model.